The overall research program in the Comparative Genomic Responses to Environmental Stressors project involves understanding contribution of environmental toxicants to the etiology of human diseases. Specifically, we are interested in understanding how organisms respond on the molecular level when they are exposed to transition metals. We have focused our research on understanding the metal-responsive regulatory processes controlling the gene expression. Ultimately, disruption of these regulatory processes or the inability of an organism to affectively respond to metal exposure may lead to the development of pathologies. We are concerned with the role of metals in the etiology of cancer; in addition, we have recently focused our research efforts on understanding how environmental agents disrupt neuronal development to affect nerve structure and the cognitive ability of an organism (e.g., neural tube defects and autism). [unreadable] [unreadable] To address these problems, our research interests are directed toward understanding the mechanisms by which metals affect the transcription of specific genes and entire genomes, activate signal transduction cascades, induce post-translational modification of metal-responsive transcription factors and disrupt normal development. Although our major focus is on the response mechanism associated with cadmium, copper and mercury exposure, we are also investigating the mechanism of global metal responsiveness by also examining silver, zinc, arsenic and chromium toxicity. To investigate these mechanisms, we use a variety of model systems, each with characteristics that make in applicable to our research: yeast (rapid growth, genetics), C. elegans (multicellular, genetics, defined cell biology), and mammalian cell culture (more applicable to human conditions). In addition, through collaborate efforts; we are utilizing zebrafish (multicellular, vertebrate) and mice (genetics, vertebrate). [unreadable] [unreadable] The research techniques that the Comparative Genomic Responses to Environmental Stressors project is applying include classic genetic and reverse-genetic approaches, RNA interference, molecular biology, protein biochemistry, traditional toxicology, cell biology, image analysis and visualization, and transcriptomics. Results from our research will be used to help elucidate the fundamental mechanisms of transition metal induced disease, developmental abnormalities and carcinogenesis; and how organisms adapt to increasingly toxic environments.[unreadable] [unreadable] To accomplish the goals of this project there several interrelated sub-projects being performed:[unreadable] [unreadable] Characterization of a cadmium-responsive gene from C. elegans.[unreadable] Mechanism of activation of the mammalian, metal-activated transcription factor, MTF-Regulation of gene expression by copper. [unreadable] Genomic response of cadmium in C. elegans. [unreadable] Comparative Genomic responses to environmental toxicants. [unreadable] Genomic responses to transition metal exposure in S. cerevisiae.